Preparation of polycarboxylic compounds

ABSTRACT

Novel methods for preparing polycarboxylic compounds which are useful as metal sequestrants and food acidulants are disclosed. These compounds are aconitic acid and a mixture of aconitic acid, and the lactones of isocitric acid and alloisocitric acid. The compounds can be neutralized to the corresponding salts which, in turn, are metal sequestering agents. The novel methods include chlorination of propane-1,1,2,3-tetracarboxylic tetraesters.

This is a continuation application of Ser. No. 47,859 filed June 12,1979 now abandoned which was a continuation application of Ser. No.905,308 filed May 12, 1978 now abandoned which was a divisionalapplication of Ser. No. 642,804 filed Dec. 22, 1975 now U.S. Pat. No.4,123,459.

This invention broadly relates to novel processes for the preparation ofaconitic acid and a mixture of aconitic acid and the lactones ofisocitric acid and alloisocitric acid. These compounds, while useful inthemselves as metal sequestering agents, may be neutralized to form thealkali metal salts corresponding to the particular compound employed.These salts are, in turn, metal sequestering agents and/or detergentbuilders. The acid forms are useful as food acidulants. The lactonecompounds may be easily converted into the corresponding hydroxy acidforms which also have utility as food acidulants.

The prior art methods of preparing aconitic acid were practicallylimited to natural fermentation and dehydration of citric acid (see U.S.Pat. No. 2,566,172; and Hentschel, J. Prakt Chem. (2) 35, 205 (1887).Although a synthetic method for aconitic acid has been proposed in thearticle by Michael, J. Prakt Chem. (2) 49, 21 (1894), this method hasnot been commercialized. Similarly synthetic methods for preparation ofthe lactones of isocitric acid and alloisocitric acid have been proposedby Pacher and Vickery, J. Biol. Chem. 163 169-184 (1946) and Gawron etal, J.A.C.S. 80 5856-5860 (1958) but do not appear to have beencommercialized.

Accordingly, an object of the present invention is to provide asynthetic process for producing aconitic acid and a mixture of aconiticacid and lactones of isocitric acid and alloisocitric acid.

A further object is to produce the above compounds by a process whichlends itself to commercial application.

Other objects and advantages will appear as the description proceeds.

The attainment of the above objects is made possible by this inventionwhich includes chlorination of a propane-1,1,2,3-tetracarboxyliccompound having the formula (I) ##STR1## wherein R independentlyrepresents a lower primary alkyl of 1-4 carbon atoms such as methyl,ethyl, propyl, and butyl, to form a chlorinated tetracarboxyliccompound. This compound is then saponified and dehydrochlorinated at apH of about 9-11 preferably by heating with an alkali metal or alkalineearth metal hydroxide at temperatures of 25°-100° C. to form a propenetetracarboxylate derivative. Acidification of this derivative below a pHof about 8 produces aconitic acid and a mixture of aconitic acid and thelactones of isocitric acid and alloisocitric acid. The aconitic acid isinitially obtained in both cis and trans forms. However, on work-up,which involves evaporation of the acidified solution to a residue, mostof the cis aconitic acid is converted to trans aconitic acid. Similarly,in the mixture where both the aconitic acid and lactones appear,isocitric acid and alloisocitric acid are obtained initially in thereaction mixture. On work-up, which involves evaporation of theacidified solution, the isocitric acid and alloisocitric acid are mainlyconverted to the lactone forms.

The subject invention, encompassing novel synthetic processes for thepreparation of aconitic acid, or a mixture of aconitic acid and theabove-described lactones, overcomes one or more of the disadvantages ofthe prior art heretofore described. This is accomplished with theadvantage that the compounds may be easily prepared in good yields.

The invention is hereinafter set forth in more detail, specific featuresthereof being particularly delineated in the appended claims.

In the practice of the present invention a tetraester of Formula I aboveis prepared. These tetraester compounds are known and can be prepared bya conventional Michael Reaction as set forth in Chapter 3, Volume 10 ofthe publication entitled "Organic Reactions", edited by Roger Adams etal and published in 1959 by John Wiley & Sons. These tetraesters ofFormula I are treated in the following manner:

The tetraester is chlorinated at a pH of about 2 to about 8 and theresulting product (Formula II) is separated from the reaction mixture:##STR2## wherein R is as previously defined. In the general case, thechloro-tetraester is then dehydrohalogenated and saponified in anaqueous medium containing an alkali metal hydroxide or calciumhydroxide, strontium hydroxide or barium hydroxide to form a mixture ofa 1,1,2,3-propene tetracarboxylate salt and a 1-hydroxypropane-1,1,2,3-tetracarboxylate salt. The mixture of salts is thenacidified and decarboxylated to produce a mixture of aconitic acid andthe above-described lactones.

In the general case under relatively stronger alkaline conditions, i.e.at a pH above about 9, the reaction of the above-described compound ofFormula II proceeds as in the reaction diagram of Table I following:

                                      TABLE I                                     __________________________________________________________________________    REACTION DIAGRAM                                                              __________________________________________________________________________     ##STR3##                                                                      ##STR4##                                                                      ##STR5##                                                                      ##STR6##                                                                      ##STR7##                                                                     __________________________________________________________________________

In the compounds, Formulas I through IV inclusive, R is as previouslydefined. M is a sodium, lithium, potassium, calcium, strontium or bariumcation and x is 1 or 2 and is equivalent to the valency of M.

In the special case where magnesium hydroxide is used, a relatively weakalkaline reagent, i.e. a pH of about 9 or less, the final product of thesame sequence of reactions is aconitic acid (Formula V) alone. Theintermediate (Formula IV) is not formed and the intermediate FormulaIII, is formed, is only transient. In this special case M is Mg and x is2 and R is as previously defined.

The compound of Formula I, as outlined in Table I, is chlorinated toform the compound of Formula II. The chlorination or reaction medium ispreferably one in which the Formula I compound dissolves to facilitate ahomogeneous reaction. However, the medium may be either water in whichcase the compound is dispersed or a cosolvent/water mixture in which thesolvent preferably is miscible with water and serves to dissolve theFormula I compound.

Alternatively, the reaction may be carried out in the absence of waterby utilizing an organic hypochlorite such as tertiary butylhypochlorite. In this case the reaction preferably is carried out in thepresence of an organic liquid which is compatible with the organichypochlorite and the compound of Formula I. This organic liquid issuitably a lower alcohol such as methanol, butanol, isobutanol,t-butanol and halogenated hydrocarbons such as carbon tetrachloride.

When the reaction medium contains water, it must contain sufficientwater to promote formation of the hypochlorous acid. This water maybeintroduced as part of a hypochlorous acid solution to be added or may bealready present in the reaction mixture which can then be treated withchlorine. Thus, the reaction medium may be all water or all cosolvent orany mixture of these. The total amount of reaction medium must be enoughto effectively disperse or dissolve the reactants. The ratio of thecompound of Formula I to the total amount of reaction medium by weightis generally about 1:1 to 1:30 and preferably about 1:1 to 1:10. Afterintroduction of the compound of Formula I into the reaction medium, asolution of a compound capable of generating HOCl is slowly added withstirring to the mixture to accomplish chlorination of the compound. Thehypochlorous acid may be conveniently generated by an acidified solutionof sodium hypochlorite. Generally, any alkali metal or alkaline earthmetal hypochlorite under acidic conditions can be utilized but thesodium salts being readily available are preferred. The solution ofsodium hypochlorite may be of any convenient concentration but dilutesolutions of about 5% to about 15% by weight being readily available arepreferred. The amount of HOCl required is about 1 to about 1.1 moles permole of the compound of Formula I. If a substantially greater ratio ofHOCl than 1.1 moles per mole of the compound of Formula I is utilized,it will not affect formation of the product but is uneconomical. Ifsubstantially less than one mole is employed, the reaction will notproceed to completion. When sodium hypochlorite is used, then aconcurrent addition of a non-oxidizing mineral acid, such as forexample, hydrochloric acid is employed to maintain a pH of less thanabout 8, preferably about 5 to about 7. If chlorine water is used, thepH is maintained below about 8, preferably about 5 to about 7 by theaddition of alkali metal carbonates or hydroxides. The above pH range isused to maintain reasonable reaction rates.

The temperature of the above-described chlorination is usually about 0°to 50° C. to avoid premature decarboxylation prior to halogenation ofthe compound. Ambient temperatures are preferred as a matter ofpracticality and to keep side reactions to a minimum.

After the addition of the reactants, the reaction may be monitored byperiodic sampling and NMR analysis since the characteristic NMRfrequency of the methylene protons will shift from high field in thecase of the compound of Formula I to a lower field as the chlorinatedcompound of Formula II is formed in the reaction medium. When thedesired amount of chlorination is obtained, the chlorinated compound ofFormula II may be isolated by conventional methods such as extraction.However, since the invention deals with a further reaction of thiscompound to produce aconitic acid (Formula V) or a mixture of aconiticacid (Formula V) and the lactones of isocitric acid (Formula VI) andalloisocitric acid (Formula VII), the reaction mixture containing thecompound II is preferably retained and heated with the desired alkalimetal or alkaline earth metal hydroxide to produce the aforesaidproducts.

Dehydrohalogenation and saponification is accomplished at a pH of about9-12, more preferably about 9-10, and at temperatures of about 25° to110° C. and preferably about 60° to 100° C. The reaction will stillproceed although more slowly at the lower temperatures. To complete thereaction, the mixture is heated for about 3-4 hours with the concurrentaddition of a selected alkali metal or alkaline earth metal hydroxidesuntil saponification is complete. At this point the product is presentas the alkaline earth metal or alkali metal salts of compound III or amixture of the salts of compounds III and IV. In the special case wheremagnesium hydroxide is used, the pH is below about 9 and the productafter dehydrohalogenation and saponification is magnesium aconitate.Conversion of magnesium aconitate or the salts of compounds III and/orIV into the final products, i.e. compounds V, VI and VII is accomplishedby acidification with dilute mineral acid at a pH of preferably lessthan about 2. In the special case where the magnesium aconitate isacidified, aconitic acid is obtained.

In the cases wherein compounds III and/or IV are present, acidificationinvolves a decarboxylation of the intermediate tetracarboxylic compoundto produce a mixture of the compounds of Formulas V, VI and VII.

The following Examples will more fully illustrate the embodiments ofthis invention. All parts and proportions referred to herein and in theappended claims are by weight unless otherwise indicated.

EXAMPLE I A. PREPARATION OF TETRAMETHYL PROPANE-1,1,2,3-TETRACARBOXYLATE##STR8##

To 200 ml of methanol is added 0.1 gram of sodium metal. After thereaction is complete, 0.1 mole of dimethyl malonate is added. Next, 0.1mole of dimethyl maleate is added and the resulting solution is refluxedfor four hours. The reaction mixture is then distilled to yield thetetraester product: b.p., 146°-150° C. (2.0-3.0 mm Hg). The structure isconfirmed by NMR analysis.

B. PREPARATION OF TETRAMETHYL PROPANE-1-CHLORO-1,1,2,3-TETRACARBOXYLATE##STR9##

27 grams of the product prepared in I-A above is dissolved in 200 ml of1:1 methanol:water by volume. 240 grams of sodium hypochlorite solution(5.2% by weight) is slowly added over a one-hour period whilemaintaining the pH at 3 to 7 by concurrent addition of dilute HCl (5%).The reaction mixture is evaporated to a syrup, which is then extractedwith ether and the ether layer evaporated. The ethereal residue isdistilled to give 26 grams (84% of theoretical yield) of product: b.p.120°-130° C. (0.15 mm Hg) and m.p. 43.5°-49.3° C. The structure isconfirmed by NMR analysis (in CDCl₃). ##STR10##

EXAMPLE II PREPARATION OF ACONITIC ACID Procedure A

Twenty six grams (0.085 mole) of product prepared as in Example I-B ismixed with 250 mls water. Thirty grams (0.5 mole) of magnesium hydroxideis slowly added during a 10 minute period. The reaction mixture isrefluxed for 4-5 hours, cooled and acidified slowly with 101 grams of25% sulfuric acid solution to a pH of 1.3. The mixture is then filtered,evaporated to dryness in vacuo and the residue extracted with acetone.The acetone solution is filtered and evaporated to dryness to give 22grams of a residue containing 41% (62.6% yield) of trans-aconitic acid(determined by NMR analysis).

EXAMPLE III PREPARATION OF A MIXTURE OF ACONITIC ACID AND THE LACTONESOF ISOCITRIC ACID AND ALLOISOCITRIC ACID Procedure A

Thirty one grams (0.1 mole) of product prepared as in Example I-B ismixed with 200 mls water. Thirty grams (0.4 mole) calcium hydroxide isadded slowly while the pH of the reaction medium is maintained at10-10.5 and the temperature is kept between 70° and 75° C. After theaddition of calcium hydroxide is complete, the reaction mixture isstirred at 75° C. for an additional two hours and then cooled. 90 gramsof a 20% by weight hydrochloric acid solution is added slowly to a pH of1.3 and the resulting solution is then filtered. The filtrate isevaporated to dryness in vacuo and the residue extracted with acetone.The acetone extract is filtered and 19.5 grams of product consisting of53.5% (60% yield) transaconitic acid and 5.8% of a mixture of lactonesof isocitric acid and alloisocitric acid.

Procedure B

Thirty one grams (0.1 mole) of the product prepared in Example I-B ismixed with 300 mls water. 79 grams of strontium hydroxide (0.65 mole) isadded slowly at 65°-70° C. while maintaining the pH at 10-10.5. Themixture is stirred for an additional three hours after the addition ofthe strontium hydroxide. The solution is cooled and 180 grams of 10%hydrochloric acid is added slowly to a pH of 1.3. The acidified solutionis next evaporated to dryness in vacuo. The residue is extracted withacetone and the acetone extract is filtered and evaporated to dryness.There is thus obtained 23 g of residue containing 45.7% (60.5% yield)trans-aconitic acid and 10.7% of a mixture of the lactones of isocitricacid and alloisocitric acid.

Procedure C

Thirty one grams (0.1 mole) of the product prepared in Example I-B ismixed with 300 mls water. Forty four grams (0.29 mole) barium oxide isadded over a 1/2 hour period while maintaining the temperature of thereaction medium at 60°-70° C. and the pH at 10-11. The mixture is heatedfor an additional two hours after all the barium oxide has been added.The mixture is then cooled and 216 grams of a 10% solution ofhydrochloric acid is added. The acidified solution is evaporated todryness to give 22.2 grams of residue containing 59.2% (75.5 yield)trans-aconitic acid and 9.8% of a mixture of the lactones of isocitricacid and alloisocitric acid.

Procedure D

Thirty one grams (0.1 mole) of the product prepared as in Example I-B ismixed with 200 mls water. Twenty three grams (0.58 mole) sodiumhydroxide in 200 mls water, is slowly added while maintaining thetemperature of the reaction medium at 70°-75° C. and the pH at 10-10.5.The solution is heated for an additional three hours until an NMR sampleshows that hydrolysis is complete. The solution is acidified slowly with162 g of 10% hydrochloric acid to give a pH of 1.2. The acidifiedsolution is evaporated to dryness in vacuo and the residue is extractedwith acetone. The acetone solution is filtered and evaporated to drynessto give 18.3 grams of a residue consisting of 53.5% (56% yield) and32.6% (35% yield) of a mixture of the lactones of isocitric acid andalloisocitric acid (determined by NMR analysis).

EXAMPLE IV A. PREPARATION OF DIBUTYL MALONATE

116 grams dimethyl malonate is dissolved in 500 mls butanol containingone gram of sodium metal. The solution is refluxed for 8 hours. Themethanol is then distilled off and the reaction mixture is neutralizedwith concentrated hydrochloric acid and filtered. The excess butanol isnext distilled off in vacuo to give a residue of 145 grams dibutylmalonate (structure verified by NMR).

B. PREPARATION OF DIBUTYL MALEATE

Seventy grams (0.63 mole) maleic anhydride is dissolved in 300 mlsn-butanol containing one gram p-toluene sulfonic acid. The solution isrefluxed for 16 hours during which the water formed is removed with aDean Stark trap. The excess butanol is then distilled in vacuo to give aresidue of 200 g of dibutyl maleate (structure verified by NMRanalysis).

C. PREPARATION OF TETRABUTYL PROPANE-1,1,2,3-TETRACARBOXYLATE

One half gram of sodium metal is dissolved in 200 mls n-butanol and tothis solution is added 108 g (0.5 mol) of dibutyl malonate. Afterreacting for five minutes, 114 grams (0.5 mole) of dibutyl maleate isadded and the reaction mixture is refluxed for 6 hours. The solution isneutralized with a few drops of conc. hydrochloric acid and thenfiltered. The excess n-butanol is distilled off in vacuo to give 213grams of a tetrabutyl propane-1,1,2,3-tetracarboxylate. The structure isconfirmed by NMR analysis (CDCl₃) ##STR11##

D. PREPARATION OF TETRABUTYL 1-CHLOROPROPANE-1,1,2,3-TETRACARBOXYLATE##STR12##

111 grams (0.28 mole) of the product prepared in Example IV-C isdissolved in a mixture of 200 mls methanol and 200 mls water. One literof 5.25% NaOCl solution is slowly added with the concurrent addition ofdilute hydrochloric acid to maintain the pH at 5-7. The resultingimmiscible liquid is extracted with carbon tetrachloride and the CCl₄extract is distilled in vacuo. A residue of 108 grams of tetrabutyl1-chloropropane-1,1,2,3-tetracarboxylate is obtained. The structure isverified by NMR analysis (CDCl₃): ##STR13##

E. PREPARATION OF A MIXTURE OF ACONITIC ACID AND THE LACTONES OFISOCITRIC ACID AND ALLOISOCITRIC ACID

25 grams (0.05 mole) of product obtained in IV-D is mixed with 100 mlswater. Twenty one grams NaOH in 100 mls H₂ O is added slowly whilemaintaining the pH at 10-11 and the temperature at 80°-85° C. 200 mlsmethanol is added to dissolve the ester and the solution is heated for 3hours. The solution is then acidified to a pH of 1.3 with dilutehydrochloric acid and evaporated to dryness. The residue is extractedwith acetone and the acetone extract (after filtering) is evaporated todryness. There is obtained nine grams of a residue consisting of 42.3%(44% yield) of trans aconitic acid and 41.3% (38% yield) of a mixture ofthe lactones of isocitric acid and alloisocitric acid.

This invention has been described with respect to certain preferredembodiments and various modifications. Variations in the light thereofwill be suggested to persons skilled in the art and are to be includedwithin the spirit and purview of this application and the scope of theappended claims.

What is claimed is:
 1. A process for preparing a mixture of aconiticacid and lactones of isocitric acid and alloisocitric acid comprisingchlorinating a compound of the formula ##STR14## wherein R independentlyrepresents a lower primary alkyl group of 1 to 4 carbon atoms in anaqueous medium with hypochlorous acid to form a chlorinated tetraester;dehydrohalogenating and saponifying said chlorinated tetraester in anaqueous medium with M/x^(+x) OH, wherein M represents a lithium, sodium,potassium calcium, strontium or barium cation and x represents 1 or 2and is equivalent to the valency of M, to form an aqueous mixture ofpropene and hydroxy propane compounds of the formulas ##EQU1##acidifying said aqueous mixture with a mineral acid to a pH of less than2 to form said aconitic acid and said lactones.
 2. A process as definedin claim 1 wherein said chlorination takes place at a pH of about 2 toabout 8 and at a temperature of about 0° C. to about 50° C.
 3. A processas defined in claim 1 wherein said dehydrohalogenation andsaponification takes place at a pH of greater than 9 and at atemperature of about 25° C. to about 110° C.
 4. A process as defined inclaim 1 wherein said M is lithium, sodium or potassium.
 5. A process asdefined in claim 4 wherein said M is sodium.